Some of the primary challenges faced by pathologists in cancer diagnoses relate to distinguishing between different types of malignancies and differentiating between benign and malignant cell proliferations.
One example of such type of challenge is in the diagnosis of lung neuroendocrine tumors, the spectrum of which includes typical carcinoid, atypical carcinoid, large cell neuroendocrine carcinoma (LCNEC) and small cell carcinoma (SCLC). This spectrum of lung neuroendocrine tumors provides a range of phenotypically distinct entities with different biological behaviors. Although various types of lung neuroendocrine tumors share common neuroendocrine features, they differ greatly in their cytogenetic and molecular characteristics, highlighting a fundamental molecular divergence among these tumors. Importantly, they exhibit different degrees of aggressiveness, with typical carcinoid and SCLC representing the two extremes of malignancy.
In the second instance, benign conditions, including inflammatory conditions, infectious processes and benign cell proliferations can be difficult to distinguish from malignancy. As one example, the positive identification of malignant cells in lung pleural tissue biopsies and in pleural effusions can be challenging, particularly when both normal and reactive mesothelial cells are present. Pathologists generally rely on characteristic histologic features to aid in differentiating between benign and malignant conditions, however benign/reactive cells can often share these histologic features with malignant cells. Furthermore, when evaluating specimens derived from biologic fluids and needle biopsies, it can be difficult to obtain specimens with sufficient morphologic detail for clinical diagnosis. Another example is in differentiating benign melanocyte nevi from malignant melanoma. Benign nevi, especially in those with atypical features can be difficult to distinguish from malignant melanoma.
Another approach, which has lately been widely used in cancer diagnostics, is molecular diagnostics. There have been described numerous molecular markers of cancer cells, such as particular abnormalities in genetic material associated with particular forms of cancer, abnormalities on the transcription level, specific profiles of the expressed proteins.
L523S protein is one of the promising molecular markers of cancer cells which can be used for the molecular cancer diagnostics. The protein is also known as K homology domain containing protein overexpressed in cancer (KOC), which has been described by Muelter-Pillasch et al. (Oncogene 1997, 14(22), pp. 2729-2733) and by Nielsen et al. (Mol. Cell Biol. 1999, 19(2), pp. 1262-1270). Nielsen et al. (Mol. Cell Biol. 1999, 19(2), pp. 1262-1270) have determined that L523S (KOC) is identical to IMP3, a member of the insulin-like growth factor II (IGF-II) mRNA-binding protein (IMP) family. The L523S protein is a 580 amino acid oncofetal RNA binding protein that has four K homology domains and that regulates insulin-like growth factor II (IGF-II) transcripts during embryogenesis. L523S is later re-expressed in a proportion of cancer cells from various types of tumors, including pancreatic and lung adenocarcinoma, and it may function in promoting tumor cell proliferation by enhancing IGF-II protein expression.
Evidence has previously been presented (for instance, in US Patent Application Publications 2003/0236209 A1, 2003/0138438 A1 and 2002/0147143 A1) indicating that L523S may also be present in colon adenocarcinomas, prostate adenocarcinomas, CML, AML, Burkitt's Lymphoma, brain tumors, retinoblastomas, ovarian tumors, teratocarcinomas, uterus myosarcomas, germ cell tumors as well as pancreatic and cervical tumor cell lines. Since it was first identified in pancreatic carcinomas by Gress, et al. (Oncogene 1996, 13, pp. 1819-1830), the marker L523S has been detected in non-small cell carcinomas of the lung as well as other human malignancies. In particular, immunohistochemical studies have indicated L523S expression is a marker of increasingly aggressive biologic potential among pancreatic ductal lesions (Istvanic et al., Mod. Pathol. 2005, 18(S1); pp. 298A-299A). Strong and diffuse immunohistochemical expression of this marker is highly sensitive for the identification of invasive carcinoma and can be found in both severely dysplastic lesions as well as carcinomas of the pancreas. In addition, Jiang et al. (Lancet Oncol. 2006, 7, pp. 556-564) have shown that L523S is expressed in renal cell carcinoma.
Various DNA encoding sequences for and amino acid sequences of L523S have been taught in U.S. Pat. Nos. 6,969,518; 6,960,570; 6,696,247; 6,531,315; 6,518,256; 6,482,597 and in United States Patent Application Publications 2003/0236209 A1; 2003/0138438 A1; 2002/0147143 A1; 2002/0115139 A1 and 2002/0052329 A1.
Using rtPCR and microarray analyses, it has been found (Wang et al., Br J Cancer 2003, 88(6), pp. 887-894) that L523S mRNA expression is minimal in many normal tissues. Importantly, however, L523S is widely expressed in many malignancies. Istvanic et al. (Mod. Pathol. 2005, 18(S1); pp. 298A-299A) have found that a subset of carcinomas from various organs—lung, pancreas, esophagus, stomach, colorectum, cervix and bladder—express the L523S protein. The restricted and relatively low level expression of L523S in a subset of normal tissue types compared to its presence in many different forms of cancer make it a potential marker of malignancy.
Despite of accumulated evidence indicating that expression of the L523S protein is associated with metastatic potential of cancer cells, full diagnostic and prognostic potential of estimating the expression of L523S protein in cells for molecular diagnostics of cancer and, thus, the value of L523S protein a cancer biomarker have not been investigated.